Water soluble farnesol analogs and their use

ABSTRACT

Farnesol analogs, along with their related products (e.g., treatment compositions, wipes, absorbent articles, etc.) and their methods of formation, are provided. The farnesol analog includes a hydrophilic end group (e.g., a hydroxyl end group or a carboxylic acid end group) attached to farnesol via a covalent linkage (e.g., an ester group or an ether group).

CROSS REFERENCE TO RELATED APPLICATION

This application is the national stage entry of International PatentApplication No. PCT/CN2012/087683 having a filing date of Dec. 27, 2012,the entire contents of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Like other species of the genus Candida, Candida albicans is a diploidfungus that grows both as yeast and filamentous cells. Morespecifically, C. albicans is a dimorphic fungus, which has both ayeast-like growth habit and a filamentous form consisting of both hyphaeand pseudohypae. C. albicans exists as part of the normal microbialflora in humans, but can produce opportunistic infections ranging fromtopical infections such as oral thrush to life-threatening disseminatedmycoses. In response to changes in its environment, C. albicans cantransition from budding yeast to its filamentous morphology. Thefilamentous morphology is important for its virulence and causes bothskin and mucosal infections. Quorum sensing has been identified as aphenomenon contributing to C. albicans' morphogenic transition from itsconidial to filamentous form.

Quorum sensing systems have been found to coordinate virulence andbiofilm development of pathogenic microorganisms. Manipulation of quorumsensing systems has been recently considered a promising strategy fordeveloping antimicrobial agents since the manipulation of quorum sensingsystems only inhibits the virulence but not the growth ofmicroorganisms.

Farnesol is an acyclic sesquiterpene alcohol (a class of terpenes) thatis naturally found in many different essential oils, including but notlimited to citronella oil, neroli oil, cyclamen oil, lemon grass oil,tuberose oil, rose oil, musk oil, and balsam and tolu oil. Generally,farnesol is an acyclic sesquiterpene alcohol found as a colorlessliquid. Farnesol is insoluble in water, but miscible with oils. Farnesolhas been found to act as a quorum sensing inhibitor to decrease the ratethat Candida albicans transitions from budding yeast to the filamentousform.

However, the practical use of farnesol as a quorum sensing inhibitorwith respect to C. albicans is particularly difficult due to itsinsoluble nature in water. That is, it is difficult to apply farnesol towipes or other materials for use, especially in a large-scalemanufacturing environment. Additionally, it is difficult to incorporatefarnesol within compositions (e.g., lotions) that can be used as aquorum sensing inhibitor, particularly when applied to the skin of auser.

As such, a need exists for a manner in which farnesol can be used as aquorum sensing inhibitor of C. albicans in a practical manner.

SUMMARY OF THE INVENTION

Farnesol analogs are generally provided, along with their relatedproducts (e.g., treatment compositions, wipes, absorbent articles,etc.). In one embodiment, the farnesol analog includes a hydrophilic endgroup (e.g., a hydroxyl end group or a carboxylic acid end group)attached to farnesol via a covalent linkage (e.g., an ester group or anether group).

In one embodiment, the farnesol analog can have the structure:

where n is an integer from 1 to about 8 (e.g., n is 2, 3, or 4), or itsdeprotonated salt.

The hydrophilic end group of the farnesol analog can, in one embodiment,comprises a second ester group. For example, the farnesol analog canhave the structure:

where n is an integer from 1 to about 8 (e.g., n is 2, 3, or 4); and mis an integer from 1 to about 8 (m is 2, 3, or 4).

In one particular embodiment, the covalent linkage of the farnesolanalog can include an ether group, and the hydrophilic end group can bea hydroxyl end group. For example, the farnesol analog can have thestructure:

where n is an integer from 1 to about 8 (e.g., n is 2, 3, or 4).Alternatively, the farnesol analog can have the structure:

where n is an integer that is 1 to about 100. In yet another alternativeembodiment, the farnesol analog can include a monosaccharide covalentlyattached to the farnesol via an ether linkage, such as the farnesolanalog having the structure:

In one particular embodiment, the farnesol analog has a solubility inwater that is 10 grams per 100 grams of water or greater.

Wipes are also generally provided that can include a web of a pluralityof fibers and coated with a treatment composition that includes such afarnesol analog.

Absorbent articles are also generally provided that can include a liquidimpermeable outer cover; a liquid permeable body side liner; anabsorbent body disposed between the outer cover and body side liner; anda treatment composition applied to the body side liner. The treatmentcomposition includes such a farnesol analog.

Methods are also generally provided for forming a farnesol analog thatis soluble in water from a farnesol molecule having a hydroxyl group.The method can, in one embodiment, include covalently attaching ahydrophilic end group (e.g., a hydroxyl end group or a carboxylic acidend group) to the farnesol molecule via reaction with its hydroxyl groupto form a covalent linkage (e.g., an ester group or an ether group).

Other features and aspects of the present invention are discussed ingreater detail below.

BRIEF DESCRIPTION OF THE DRAWINGS

A full and enabling disclosure of the present invention, including thebest mode thereof, directed to one of ordinary skill in the art, is setforth more particularly in the remainder of the specification, whichmakes reference to the appended figures in which:

FIG. 1 is a perspective view of an exemplary feminine care absorbentarticle;

FIG. 2 is a cross-sectional view of the article of FIG. 1 taken alongthe lines indicated in FIG. 1;

FIG. 3 shows a graph of the growth and percentage of singlet cells of C.albicans SC5314 in YPD and mGSB broths incubated at 30° C. according tothe Examples;

FIG. 4 shows the effect of farnesol (100 μM) and tyrosol (100 μM) on thelag phase of C. albicans SC5314 in YPD medium at 37° C. according to theExamples; and

FIG. 5 shows the reaction synthesis pathways used to form the exemplaryfarnesol analogs according to the Examples.

Repeat use of references characters in the present specification anddrawings is intended to represent the same or analogous features orelements of the invention.

DETAILED DESCRIPTION OF REPRESENTATIVE EMBODIMENTS

Reference now will be made in detail to various embodiments of theinvention, one or more examples of which are set forth below. Eachexample is provided by way of explanation of the invention, notlimitation of the invention. In fact, it will be apparent to thoseskilled in the art that various modifications and variations may be madein the present invention without departing from the scope or spirit ofthe invention. For instance, features illustrated or described as partof one embodiment, may be used on another embodiment to yield a stillfurther embodiment. Thus, it is intended that the present inventioncovers such modifications and variations as come within the scope of theappended claims and their equivalents.

Methods are generally provided for modifying farnesol to be morehydrophilic, along with the resulting farnesol analogs. Uses of suchfarnesol analogs are also generally provided in a treatment composition(e.g., a lotion) and as an additive to a wipe and/or an absorbentarticle. In one particular embodiment, the farnesol analogs cangenerally act as a quorum sensing inhibitor to decrease the rate thatCandida albicans, and other species of the genus Candida, transitionsfrom budding yeast to the filamentous form. Although referred tohereafter with respect to Candida albicans, the presently disclosedcompositions, methods, and farnesol analogs are also applicable to otherspecies of yeast within the genus Candida (e.g., C. glabrata, C. rugosa,C. parapsilosis, C. tropicalis, and C. dubliniensis, and C. oleophila).

Thus, the farnesol analogs can serve as an inhibitor of infection byCandida albicans on the skin of the user, when applied within a lotion,via a wipe, or when included on an absorbent article in a manner thatcan contact or be in close proximity to the skin of the wearer.

When applied to C. albicans, the farnesol analog can, in certainembodiments, have a percentage of cells with germ tubes formed (GTF %)of less than about 50%, such as less than about 25%.

I. Methods of Modifying Farnesol

Farnesol is a natural organic compound that is insoluble in water. Itcan be readily isolated from its natural sources (e.g., essential oils),or can be synthetically formed. Farnesol has the chemical structureshown below:

Due to the presence of the hydroxyl end group (i.e., —OH), a hydrophilicend group can be readily attached through reaction of the hydroxyl groupvia any number of reactions suitable for aliphatic alcohols. Forexample, acid-base reactions, esterification reactions, etherification,substitution, elimination, etc. can be utilized to attach a hydrophilicend group onto the farnesol to form an analog.

By adding the polar, hydrophilic end groups, the farnesol analog becomesmuch more like a non-ionic surfactant comprised of a hydrophobic tail(the terpenoid chain) and a hydrophilic head group (the added endgroup). With this chemical structure, the farnseol analog is prone toacting like a surface active agent (surfactant) and can thus organize inmicelles, bilayers, or any of the other known surfactant phases. Whilethe modified oil is generally water soluble, micelles may form in thewater solution. However, no separate phase is detected in the solution.For example, the farnesol analog can have a solubility in water of about10 grams per 100 grams of water or greater due to the presence of thehydrophilic end group (e.g., a hydroxyl end group, a carboxylic acid endgroup, etc.) and/or a polar linkage (e.g., an ester, an ether, etc.).

A. Farnesol Analogs Having at Least One Ester Linkage

In one particular embodiment, a carboxylic acid functional molecule canbe reacted with the hydroxyl end group of the farnesol molecule throughan esterification reaction. As such, a hydrophilic end group can beattached to farnesol via an ester linkage (i.e., —COO—).

In addition to the carboxylic group, the carboxylic acid functionalmolecule can also include a hydrophilic chain. As such, following theesterification reaction, the hydrophilic chain is covalently attached tothe components of the reactive product via an ester group and optionallyan alkane chain (e.g., having 1 to about 8 carbon atoms, such as 1 toabout 4 carbons).

In one particular embodiment, the carboxylic acid functional molecule isa dicarboxylic acid, such as oxalic acid, malonic acid, succinic acid,glutaric acid, adipic acid, pimelic acid, suberic acid, tartaric acid,etc. As such, following the esterification reaction, a carboxylic acidgroup is covalently attached to the farnesol via an ester group and analkane chain (e.g., having 1 to about 8 carbon atoms, such as 1 to about4 carbon atoms). Such a farnesol analog can be represented by theformula:

where n is 1 to about 8, such as 1 to 4 (e.g., 2, 3, or 4), along withtheir related deprotonated salts. For example, farnesol can be reactedwith succinic acid through an esterification reaction (e.g., utilizingcommon esterification conditions such as acid catalysis, solid-supportedacid catalysis like 1 mol % HClO₄—SiO₂, diethylazodicarboxylate/triphenylphosphine (DEAD/PPh₃),dicyclohexylcarbodiimide/4-N,N-dimethylaminopyridine (DCC/DMAP),4-(1-pyrrolidinyl)pyridine, or various Lewis acid catalysts) to form afarnesol analog having a carboxylic acid group covalently attached tothe farnesol terpenoid chain via an ester group and an alkane chain oftwo carbon atoms, as shown in Farnesol Analog 1 represented below, whichis intended to include its deprotonated salt:

Exemplary Farnesol Analog 1 can then be rendered water soluble byraising the pH above the pKa of the Exemplary Farnesol Analog 1 togenerate its deprotonated carboxylic salt.

Optionally, when the farnesol analog defines a carboxylic acidfunctional group (such as shown in Formula 1 and exemplary farnesolanalog 1), a second esterification reaction with an alcohol can beutilized to form a second ester linkage to a hydrophilic end group. Inone embodiment, a glycol can be reacted with the carboxylic acidfunctional farnesol analog (e.g., as in Formula 1) to attach a hydroxylend group via a second ester linkage. Glycols refer generally to a classof organic compounds having two hydroxyl (—OH) groups attached todifferent carbon atoms. Particularly suitable glycols include, but arenot limited to, ethylene glycol, propylene glycol, and butane-1,4-diol.

For example, an esterification reaction can be utilized to react thecarboxylic acid functional farnesol analog shown in Formula 1 with aglycol to form a farnesol analog having a hydroxyl group covalentlyattached via two ester linkages, optionally a first alkane chain (e.g.,having 1 to about 8 carbon atoms, such as 1 to about 4 carbon atoms),and optionally a second alkane chain (e.g., having 1 to about 4 carbonatoms, such as 2 or 3 carbon atoms). Such a farnesol analog can berepresented by the formula, along with their deprotonated salts:

where n is 1 to about 8 (e.g., 1 to about 4) and m is 1 to about 8(e.g., 2, 3, or 4). In particular embodiments, n can be 2 or 3 or 4 andm can be 2 or 3 or 4. For example, particularly suitable farnesolanalogs having a hydroxyl end group attached via two ester linkages, afirst alkane chain of 2 carbon atoms (i.e., n is 2), and a second alkanechain of 4, 3, and 2 carbon atoms are shown, respectively, below as theexemplary farnasol analogs 2, 3, and 4:

As such, in these embodiments, the hydrophilic end group contains atleast one hydroxyl group (—OH) along the chain (e.g., a terminalhydroxyl group) and at least two ester linkages. Without wishing to bebound by any particular theory, it is believed that the presence ofpolar groups, such as hydroxyl group(s) and/or ester linkage(s), allowsfor the farnesol analog to be more soluble in water.

B. Farnesol Analogs Having a Carbonyl Linkage

In another embodiment, a hydrophilic end group can be covalentlyattached to the farnesol molecule through an ether linkage (i.e.,—C—O—C—). For instance, the farnesol analog can have a hydrophilic groupwith a hydroxyl end group and an alkane chain having 1 to about 8carbons (e.g., 1 to about 4 carbons) attached via an ether linkage. Sucha farnesol analog can be represented by the formula, along with theirdeprotonated salts:

wherein is 1 to about 8 (e.g., 2, 3, or 4).

In particular embodiments, n can be 2 or 3 or 4. For example,particularly suitable farnesol analogs having a hydroxyl end groupattached via an ether linkage and an alkane chain of 4, 3, and 2 carbonatoms are shown, respectively, below as the exemplary farnasol analogs5, 6, and 7:

In one embodiment, for instance, farnesol can be reacted with anotheralcohol (e.g., a glycol) via a dehydration reaction to form an etherlinkage to an alkane chain having a hydroxyl end group. For instance, aglycol (e.g., ethylene glycol, propylene glycol, etc.) can be reactedwith the hydroxyl group of the farnesol to attach a hydroxyl end groupvia an ether linkage and an alkane chain having 1 to about 8 carbons(e.g., 1 to about 4 carbons), as shown in Formula 3 above. For example,particularly suitable dehydration reactions can be performed at elevatedtemperatures (e.g., about 125° C. or more), while catalyzed by anacid(s), such as sulfuric acid.

Other types of ether forming reactions can include so-called “Williamsonether synthesis,” which involves treatment of farnesol with a strongbase to replace the hydrogen of the hydroxyl group with a suitablecation forming analkoxide analog of farnasol. Then, an appropriatealiphatic compound having a suitable leaving group (R—X) at one end anda hydroxyl group (—OH) at the other end of the chain (e.g., generallyX—R—OH, where X is the leaving group and R represents an alkane chain of1 to about 8 carbons, as discussed above with reference to n in Formula3). Particularly suitable leaving groups (X) include halides (e.g.,iodide, bromide, etc.), sulfonates, and the like.

As such, in these embodiments, the hydrophilic end group contains atleast one hydroxyl group (—OH) along the chain (e.g., a terminalhydroxyl group) and at least one ether linkage. Without wishing to bebound by any particular theory, it is believed that the presence ofpolar groups, such as hydroxyl group(s) and/or ether linkage(s), allowsfor the farnesol analog to be more soluble in water.

Polyalkyleneoxide farnesol analogs can also be formed by treating analkaline solution of farnesol with alkylene oxide (e.g., ethylene oxidegas) in the appropriate molar ratio depending on the desired length (orrepeating units) of the alkylene oxide group. For example, thepolyalkyleneoxide farnesol analog can be a polyethyleneoxide farnesolanalog represented by the formula, along with the related deprotonatedsalts:

wherein is an integer that is 1 to about 100 (e.g., 2 to about 20, suchas 2 to about 5).

C. Attachment of a Sugar to Farnesol

In one embodiment, a sugar can be covalently attached to the farnesol,such as via an ether linkage. For example, the sugar can be amonosaccharide end group (e.g., glucose, fructose, galactose, xylose,ribose, etc) or a disaccharide end group (e.g., sucrose).

Such an analog can be formed, for example, via a two-step reaction: (1)convertingthe hydroxyl group of the farnesol to a halide viaN-bromosuccinimide (NBS), (2) followed by a SN₂ displacement reaction ofthe protected sugar with the halogenated farnesol. The protecting groupsare then removed from the sugar following standard protocols.

For example, exemplary farnesol analog 8 shows a glucose end groupattached to the farnesol via an ether linkage:

Such a farnesol analog, having a monosaccharide covalently attached tothe farnesol via an ether linkage, defines a plurality of hydroxylgroups (—OH) and ether groups in its hydrophilic end group. This highconcentration of polar groups can help increase the solubility of thefarnesol analog in water.

II. Treatment Composition

The farnesol analog can be included within a treatment composition,which can be, for example, applied to the skin of a user. For example,the treatment composition may be administered to the skin of the user ina variety of forms, such as a lotion, cream, jelly, liniment, ointment,salve, oil, foam, gel, film, wash, coating, liquid, capsule, tablet,concentrate, etc.

The manner in which the treatment composition is formed may vary as isknown to those skilled in the art. In one embodiment, for example, thefarnesol analog may be initially blended with a solvent, such as waterand/or an organic solvent. Organic solvents can be present, such asalcohols, such as methanol, ethanol, n-propanol, isopropanol, butanol,and so forth; triglycerides; ketones (e.g., acetone, methyl ethylketone, and methyl isobutyl ketone); esters (e.g., ethyl acetate, butylacetate, diethylene glycol ether acetate, and methoxypropyl acetate);amides (e.g., dimethylformamide, dimethylacetamide,dimethylcaprylic/capric fatty acid amide and N-alkylpyrrolidones);nitriles (e.g., acetonitrile, propionitrile, butyronitrile andbenzonitrile); sulfoxides or sulfones (e.g., dimethyl sulfoxide (DMSO)and sulfolane); and so forth. The combination of the ingredients may befacilitated through agitation (e.g., stirring) and control of thetemperatures of each mixture. Conventional homogenization techniquesmay, for instance, be employed to stabilize the treatment composition.

The resulting treatment composition may contain a discontinuous oilphase dispersed within a continuous solvent phase. Nevertheless, due tothe stability imparted by the hydrophilic end group on the farnesolanalog, a relatively small amount of the farnesol analog may be employedand still achieve the desired quorum sensing inhibition of C. albicans.More particularly, the coating solution may employ farnesol analogs inan amount of from about 0.05 wt. % to about 15 wt. %, in someembodiments from about 0.1 wt. % to about 10 wt. %, and in someembodiments, from about 0.5 wt. % to about 5 wt %. For example, in oneparticular embodiment, the coating solution may employ farnesol analogsin a relatively small amount, while still achieving the desired quorumsensing inhibition, such as in an amount of from about 0.01 wt. % toabout 1 wt. % (e.g., about 0.05 wt. % to about 0.5 wt. %).

Other additives may also be incorporated into the treatment composition.For example, the composition may contain a preservative or preservativesystem to inhibit the growth of microorganisms over an extended periodof time. Suitable preservatives may include, for instance, alkanols,disodium EDTA (ethylenediamine tetraacetatic acid), EDTA salts, EDTAfatty acid conjugates, isothiazolinones, phenoxyethanol, phenethylalcohol, caprylyl glycol, 1,2-hexanediol, benzoic esters (parabens)(e.g., methylparaben, propylparaben, butylparaben, ethylparaben,isopropylparaben, isobutylparaben, benzylparaben, sodium methylparaben,and sodium propylparaben), benzoic acid, propylene glycols, sorbates,urea derivatives (e.g., diazolindinyl urea), and so forth. Othersuitable preservatives include those sold by Sutton Labs, such as“Germall 115” (amidazolidinyl urea), “Germall II” (diazolidinyl urea),and “Germall Plus” (diazolidinyl urea and iodopropynyl butylcarbonate).Another suitable preservative is Kathon CG®, which is a mixture ofmethylchloroisothiazolinone and methylisothiazolinone available from DowChemical; Mackstat H 66 (available from Rhodia, part of the SolvayGroup). Still another suitable preservative system is a combination of56% propylene glycol, 30% diazolidinyl urea, 11% methylparaben, and 3%propylparaben available under the name GERMABEN® II from Ashland.

The pH of the composition may also be controlled within a range that isconsidered more biocompatible. For instance, it is typically desiredthat the pH is within a range of from about 3 to about 9, in someembodiments from about 4 to about 8, and in some embodiments, from about5 to about 7. Various pH modifiers may be utilized in the composition toachieve the desired pH level. Some examples of pH modifiers that may beused in the present invention include, but are not limited to, mineralacids, sulfonic acids (e.g., 2-[N-morpholino]ethane sulfonic acid),carboxylic acids, and polymeric acids. Specific examples of suitablemineral acids are hydrochloric acid, nitric acid, phosphoric acid, andsulfuric acid. Specific examples of suitable carboxylic acids are lacticacid, acetic acid, citric acid, glycolic acid, maleic acid, gallic acid,malic acid, succinic acid, glutaric acid, benzoic acid, malonic acid,salicylic acid, gluconic acid, and mixtures thereof. Specific examplesof suitable polymeric acids include straight-chain poly(acrylic) acidand its copolymers (e.g., maleic-acrylic, sulfonic-acrylic, andstyrene-acrylic copolymers), cross-linked polyacrylic acids having amolecular weight of less than about 250,000, poly(methacrylic) acid, andnaturally occurring polymeric acids such as carageenic acid,carboxymethyl cellulose, and alginic acid. Basic pH modifiers may alsobe used in some embodiments of the present invention to provide a higherpH value. Suitable pH modifiers may include, but are not limited to,ammonia; mono-, di-, and tri-alkyl amines; mono-, di-, andtri-alkanolamines; alkali metal and alkaline earth metal hydroxides;alkali metal and alkaline earth metal silicates; and mixtures thereof.Specific examples of basic pH modifiers are ammonia; sodium, potassium,and lithium hydroxide; sodium, potassium, and lithium metasilicates;monoethanolamine; triethylamine; isopropanolamine; diethanolamine; andtriethanolamine. When utilized, the pH modifier may be present in anyeffective amount needed to achieve the desired pH level.

To better enhance the benefits to consumers, other optional ingredientsmay also be used. For instance, some classes of ingredients that may beused include, but are not limited to: antioxidants (product integrity);anti-reddening agents, such as aloe extract; astringents—cosmetic(induce a tightening or tingling sensation on skin); colorants (impartcolor to the product); deodorants (reduce or eliminate unpleasant odorand protect against the formation of malodor on body surfaces, by, forexample, absorption, adsorption, or masking); fragrances (consumerappeal); opacifiers (reduce the clarity or transparent appearance of theproduct); skin conditioning agents; skin exfoliating agents (ingredientsthat increase the rate of skin cell turnover such as alpha hydroxy acidsand beta hydroxyacids); skin protectants (a drug product which protectsinjured or exposed skin or mucous membrane surface from harmful orannoying stimuli); and viscosity modifiers (e.g., thickeners to increaseviscosity).

III. Wipe

In one embodiment, the treatment composition can be applied to a wipeprior to use. Such wipes may be used to reduce microbial or viralpopulations on a hard surface (e.g., sink, table, counter, sign, and soforth) or surface on a user/patient (e.g., skin, mucosal membrane, suchas in the mouth, nasal passage, vagina, the area surrounding the vaginalopening, etc., wound site, surgical site, and so forth). The wipe mayprovide an increased surface area to facilitate contact of thecomposition with microorganisms. In addition, the wipe may also serveother purposes, such as providing water absorption, barrier properties,etc. The wipe may also eliminate microorganisms through shear forcesimparted to the surface.

The wipe may be formed from any of a variety of materials as are wellknown in the art. For example, the wipe can include a nonwoven fabric,woven fabric, knit fabric, wet-strength paper, or combinations/laminatesthereof. Materials and processes suitable for forming such substrate arewell known to those skilled in the art. For instance, some examples ofnonwoven fabrics that may be used as the wipe in the present disclosureinclude, but are not limited to, spun bonded webs (apertured ornon-apertured), meltblown webs, bonded carded webs, air-laid webs,coform webs, hydraulically entangled webs, and the like. In addition,nonwoven fabrics can contain synthetic fibers (e.g., polyethylenes,polypropylenes, polyvinyl chlorides, polyvinylidene chlorides,polystyrenes, polyesters, polyamides, polyimides, etc.); cellulosicfibers (softwood pulp, hardwood pulp, thermomechanical pulp, etc.); orcombinations thereof.

In one particular embodiment, the wipe includes a fibrous web thatcontains absorbent fibers. For example, the wipe may be a cellulosebased paper product containing one or more paper webs, such as facialtissue, bath tissue, paper towels, napkins, and so forth. The paperproduct may be single-ply in which the web forming the product includesa single layer or is stratified (i.e., has multiple layers), ormulti-ply, in which the webs forming the product may themselves beeither single or multi-layered. Normally, the basis weight of such apaper product is less than about 120 grams per square meter (“gsm”), insome embodiments less than about 80 gsm, in some embodiments less thanabout 60 gsm, and in some embodiments, from about 10 to about 60 gsm.

Any of a variety of materials can also be used to form the paper web(s)of the product. For example, the material used to make the paper productmay include absorbent fibers formed by a variety of pulping processes,such as kraft pulp, sulfite pulp, thermomechanical pulp, etc. The pulpfibers may include softwood fibers having an average fiber length ofgreater than 1 mm and particularly from about 2 to 5 mm based on alength-weighted average. Such softwood fibers can include, but are notlimited to, northern softwood, southern softwood, redwood, red cedar,hemlock, pine (e.g., southern pines), spruce (e.g., black spruce),combinations thereof, and so forth. Hardwood fibers, such as eucalyptus,maple, birch, aspen, and so forth, can also be used. In certaininstances, eucalyptus fibers may be particularly desired to increase thesoftness of the web. Eucalyptus fibers can also enhance the brightness,increase the opacity, and change the pore structure of the web toincrease its wicking ability. Moreover, if desired, secondary fibersobtained from recycled materials may be used, such as fiber pulp fromsources such as, for example, newsprint, reclaimed paperboard, andoffice waste. Further, other natural fibers can also be used in thepresent invention, such as abaca, sabai grass, milkweed floss, pineappleleaf, bamboo, algae, and so forth. In addition, in some instances,synthetic fibers can also be utilized.

If desired, the absorbent fibers (e.g., pulp fibers) may be integratedwith synthetic fibers to form a composite. Synthetic thermoplasticfibers may also be employed in the nonwoven web, such as those formedfrom polyolefins, e.g., polyethylene, polypropylene, polybutylene, etc.;polytetrafluoroethylene; polyesters, e.g., polyethylene terephthalateand so forth; polyvinyl acetate; polyvinyl chloride acetate; polyvinylbutyral; acrylic resins, e.g., polyacrylate, polymethylacrylate,polymethylmethacrylate, and so forth; polyamides, e.g., nylon; polyvinylchloride; polyvinylidene chloride; polystyrene; polyvinyl alcohol;polyurethanes; polylactic acid; polyhydroxyalkanoate; copolymersthereof; and so forth. Because many synthetic thermoplastic fibers areinherently hydrophobic (i.e., non-wettable), such fibers may optionallybe rendered more hydrophilic (i.e., wettable) by treatment with asurfactant solution before, during, and/or after web formation. Otherknown methods for increasing wettability may also be employed, such asdescribed in U.S. Pat. No. 5,057,361 to Sayovitz, et al., which isincorporated herein by reference. The relative percentages of suchfibers may vary over a wide range depending on the desiredcharacteristics of the composite. For example, the composite may containfrom about 1 wt. % to about 60 wt. %, in some embodiments from 5 wt. %to about 50 wt. %, and in some embodiments, from about 10 wt. % to about40 wt. % synthetic polymeric fibers. The composite may likewise containfrom about 40 wt. % to about 99 wt. %, in some embodiments from 50 wt. %to about 95 wt. %, and in some embodiments, from about 60 wt. % to about90 wt. % absorbent fibers.

Composites, such as described above, may be formed using a variety ofknown techniques. For example, a nonwoven composite may be formed thatis a “coform material” that contains a mixture or stabilized matrix ofthermoplastic fibers and a second non-thermoplastic material. As anexample, coform materials may be made by a process in which at least onemeltblown die head is arranged near a chute through which othermaterials are added to the web while it is forming. Such other materialsmay include, but are not limited to, fibrous organic materials such aswoody or non-woody pulp such as cotton, rayon, recycled paper, pulpfluff and also super absorbent particles, inorganic and/or organicabsorbent materials, treated polymeric staple fibers and so forth. Someexamples of such coform materials are disclosed in U.S. Pat. No.4,100,324 to Anderson, et al.; U.S. Pat. No. 5,284,703 to Everhart, etal.; and U.S. Pat. No. 5,350,624 to Georger, et al.; which areincorporated herein by reference. Alternatively, the nonwoven compositemay be formed by hydraulically entangling staple length fibers and/orfilaments with high-pressure jet streams of water. Various techniquesfor hydraulically entangling fibers are generally disclosed, forexample, in U.S. Pat. No. 3,494,821 to Evans and U.S. Pat. No. 4,144,370to Boulton, which are incorporated herein by reference. Hydraulicallyentangled nonwoven composites of continuous filaments (e.g., spunbondweb) and natural fibers (e.g., pulp) are disclosed, for example, in U.S.Pat. No. 5,284,703 to Everhart, et al. and U.S. Pat. No. 6,315,864 toAnderson, et al., which are incorporated herein by reference.Hydraulically entangled nonwoven composites of staple fiber blends(e.g., polyester and rayon) and natural fibers (e.g., pulp), also knownas “spunlaced” fabrics, are described, for example, in U.S. Pat. No.5,240,764 to Haid, et al., which is incorporated herein by reference.

Regardless of the materials or processes utilized to form the wipe, thebasis weight of the wipe is typically from about 20 to about 200 gsm,and in some embodiments, between about 35 to about 100 gsm. Lower basisweight products may be particularly well suited for use as light dutywipes, while higher basis weight products may be better adapted for useas industrial wipes.

The wipe may assume a variety of shapes, including but not limited to,generally circular, oval, square, rectangular, or irregularly shaped.Each individual wipe may be arranged in a folded configuration andstacked one on top of the other to provide a stack of wet wipes. Suchfolded configurations are well known to those skilled in the art andinclude c-folded, z-folded, quarter-folded configurations and so forth.For example, the wipe may have an unfolded length of from about 2.0 toabout 80.0 centimeters, and in some embodiments, from about 10.0 toabout 25.0 centimeters. The wipes may likewise have an unfolded width offrom about 2.0 to about 80.0 centimeters, and in some embodiments, fromabout 10.0 to about 25.0 centimeters. The stack of folded wipes may beplaced in the interior of a container, such as a plastic tub, to providea package of wipes for eventual sale to the consumer. Alternatively, thewipes may include a continuous strip of material which has perforationsbetween each wipe and which may be arranged in a stack or wound into aroll for dispensing. Various suitable dispensers, containers, andsystems for delivering wipes are described in U.S. Pat. No. 5,785,179 toBuczwinski, et al.; U.S. Pat. No. 5,964,351 to Zander; U.S. Pat. No.6,030,331 to Zander; U.S. Pat. No. 6,158,614 to Haynes, et al.; U.S.Pat. No. 6,269,969 to Huang, et al.; U.S. Pat. No. 6,269,970 to Huang,et al.; and U.S. Pat. No. 6,273,359 to Newman, et al., which areincorporated herein by reference.

The treatment composition may be impregnated into the wipe during itsformation or simply coated onto all or a portion of a surface of thewipe using known techniques, such as printing, dipping, spraying, meltextruding, coating (e.g., solvent coating, powder coating, brushcoating, etc.), foaming, and so forth. Due to the increased solubilityin water, the farnesol analog allows the treatment composition to bemore compatible for application to the wipe using such conventionalcoating techniques.

In one embodiment, for example, the coating is applied to the wipe bydipping, spraying, or printing. In one embodiment, a benefit can beachieved by applying the treatment composition in a film-like patternthat is discontinuous over the surface of the wipe. The pattern may, forexample, cover only from about 5% to about 95%, in some embodiments fromabout 10% to about 90%, and in some embodiments, from about 20% to about75% of a surface of the wipe. Such patterned application may havevarious benefits, including enhanced softness and drape, improvedabsorbency, etc.

If desired, the wipe may be dried at a certain temperature to drive thesolvents from the solution and form a concentrate. Such concentratesgenerally have a very high stability in storage. To use the wipe, wateror an aqueous solution may simply be added, thereby releasing thefarnesol analog and optionally re-emulsifying the concentrate. Dryingmay be accomplished using any known technique, such as an oven, dryingrolls (e.g., through-air drying, Yankee dryer), etc. The temperature atwhich the wipe is dried generally depends on the time period over whichit is dried, but is typically at least about 20° C., and in someembodiments, from about 30° C. to about 100° C. Drying may occur eitherbefore or after the solution is applied to the wipe. The solvent contentof the resulting concentrate is thus typically less than about 5 wt. %,in some embodiments less than about 2 wt. %, and in some embodiments,less about 1 wt. %.

The solids add-on level of the treatment composition is typically fromabout 2 to about 100%, in some embodiments from about 10% to about 80%,and in some embodiments, from about 15% to about 70%. The “solids add-onlevel” is determined by subtracting the weight of the untreatedsubstrate from the weight of the treated substrate (after drying),dividing this calculated weight by the weight of the untreatedsubstrate, and then multiplying by 100%. Lower add-on levels may provideoptimum functionality of the substrate, while higher add-on levels mayprovide optimum antimicrobial efficacy. In such embodiments, thetreatment composition typically contains farnesol analogs in an amountof from about 0.05 wt. % to about 50 wt. %, in some embodiments fromabout 1 wt. % to about 40 wt. %, and in some embodiments, from about 5wt. % to about 30 wt. %.

In addition to being employed as a treatment composition, the farnesolanalog may also be in the form of a liquid. This may be accomplished bysimply not drying the solution after it is applied to the wipe. Whilethe solids add-on level of such “wet wipes” generally remain within theranges noted above, the total amount of the solution employed in such“wet wipes” (including any solvents) depends in part upon the type ofwipe material utilized, the type of container used to store the wipes,the nature of the solution, and the desired end use of the wipes.Generally, however, each wet wipe contains from about 150 wt. % to about600 wt. %, and desirably from about 300 wt. % to about 500 wt. % of thesolution on the dry weight of the wipe.

In one embodiment, the liquid component of the wet wipe may includewater, a surfactant or surfactant system, a preservative, an optional pHmodifier (e.g., buffering agent), and the farnesol analog. For instance,the liquid component can be at least 95% by weight water (e.g., about97.5% to about 99% by weight), about 0.25 to about 1.5% by weight of asurfactant(s) (e.g., sodium lauryl glucose carboxylate, laurylglucoside, sodium lauroyl sarcosinate, a polysorbate surfactant such aspolysorbate 20, or combinations thereof), about 0.05% to about 1.0% byweight of a preservative(s) (e.g., methylisothiazolinone, sodiumbenzoate, or mixtures thereof), up to about 1.5% by weight of a pHmodifier (e.g., malic acid), and up to about 2.5% by weight of thefarnesol analog (e.g., about 0.01% by weight to about 0.5% by weight).

The present inventors have discovered that the treatment compositionincluding the farnesol analog may inhibit (e.g., reduce by a measurableamount or to prevent entirely) transition of Candida albicans frombudding yeast to the filamentous form by serving as a quorum sensinginhibitor.

IV. Absorbent Articles

Referring to FIGS. 1 and 2, a typical feminine care absorbent article10, such as a pad or liner, is shown. The article 10 includeslongitudinal ends 24 and 26 and opposed longitudinal sides 28 and 30,and is designed to extend through the wearer's crotch region between thelegs upon the inside surface of an undergarment. FIG. 2 is a cut-awayview of the article 10. In this view, it can be seen that the article 10includes a substantially liquid impermeable outer cover 12, and anabsorbent structure in superposed relation to the outer cover 12. Theabsorbent structure may include various layers and/or components. Thetopmost component defines a body facing surface 16 that is disposedagainst the wearer's skin. In the illustrated embodiment, the absorbentstructure includes a porous, liquid permeable body side liner 14defining the body facing surface 16, and an absorbent body 18, such asan absorbent pad, disposed between the outer cover 12 and body sideliner 14. The body side liner 14 is generally superimposed andcoextensive with the outer cover 12, but may cover an area which islarger or smaller than the area of the outer cover 12. The body sideliner 14, outer cover 12, and absorbent body 18 are integrally assembledtogether employing suitable attachment means, such as adhesive,ultrasonic bonds, thermal bonds, etc. In the shown embodiment, the bodyside liner 14 and outer cover 12 are bonded together and to theabsorbent body 18 with an adhesive, such as a hot melt,pressure-sensitive adhesive. The body side liner 14 is bonded to theouter cover 12 around the periphery of the article 10 to form aperiphery margin area 13. In other embodiments, the outer cover 12 andbody side liner 14 may have a periphery that is continuous with the edgeof the absorbent body 18.

The outer cover 12 is desirably formed of a breathable material whichpermits vapors to escape from the absorbent body 18 while stillpreventing liquid exudates from passing through the outer cover 12. Forexample, in one particular embodiment, the outer cover 12 is formed by amicroporous film/nonwoven laminate including a spunbond nonwovenmaterial laminated to a microporous film. Suitable materials for theouter cover 12 are well known to those skilled in the art and many suchmaterials are described, for example, in detail in U.S. Pat. No.6,149,934 of Krzysik, et al., which is incorporated by reference herein.Reference is also made to U.S. Pat. No. 5,879,341 of Odorzynski, et al.;U.S. Pat. No. 5,843,056 of Good, et al.; and U.S. Pat. No. 5,855,999 ofMcCormack, which are incorporated by reference herein, for descriptionsof suitable breathable materials for the outer cover 12.

The body side liner 14 presents the body facing surface 16 which iscompliant, soft, and nonirritating to the wearer's skin. The body sideliner 14 helps to isolate the wearer's skin from liquids held in theabsorbent body 18. Further, the body side liner 14 may be lesshydrophilic than the absorbent body 18 to present a relatively drysurface to the wearer, and may be sufficiently porous to be liquidpermeable so that liquid readily penetrates its thickness to be absorbedby the absorbent body 18. A suitable body side liner 14 may be made froma wide selection of materials, such as porous foams, reticulated foams,apertured plastic films, natural fibers, synthetic fibers, or anycombination thereof. Various woven and nonwoven fabrics can be used forthe body side liner 14. For example, the liner 14 may be composed of ameltblown or spunbonded web of polyolefin fibers. The body side liner 14may also be a bonded-carded web of natural and/or synthetic fibers. Theliner may be composed of a substantially hydrophobic material which,optionally, may be treated with a surfactant, a wetting agent, orotherwise processed to impart a desired level of wettability andhydrophilicity. The liner can be treated with a surfactant that includesa skin wellness treatment. This treatment can be applied in conjunctionwith a surfactant(s) or as a separate treatment.

The absorbent body 18 may comprise a matrix of hydrophilic fibers, suchas a web of cellulosic fluff, alone or mixed with particles of ahigh-absorbency material commonly known as “superabsorbent material.”The wood pulp fluff may be exchanged with synthetic, polymeric,meltblown fibers or with a combination of meltblown fibers and naturalfibers. The superabsorbent particles may be substantially homogeneouslymixed with the hydrophilic fibers or may be non-uniformly mixed. Thefluff and superabsorbent particles may be selectively placed intodesired zones of the absorbent body 18 to better contain and absorb bodyexudates. Alternatively, the absorbent body 18 may include a laminate offibrous webs and/or fibrous webs and superabsorbent materials or othersuitable means of maintaining a superabsorbent material in a localizedarea.

The high absorbency material can be selected from natural, synthetic,and modified natural polymers and materials. The high absorbencymaterials can be inorganic materials, such as silica gels, or organiccompounds, such as crosslinked polymers. The term “crosslinked” refersto any means for effectively rendering normally water-soluble materialssubstantially water insoluble but swellable. Such means can include, forexample, physical entanglement, crystalline domains, covalent bonds,ionic complexes and associations, hydrophilic associations such ashydrogen bonding, and hydrophobic associations or Van der Waals forces.

Examples of synthetic, polymeric, high absorbency materials include thealkali metal and ammonium salts of poly(acrylic acid) andpoly(methacrylic acid), poly(acrylamides), poly(vinyl ethers), maleicanhydride copolymers with vinyl ethers and alpha-olefins, poly(vinylpyrolidone), poly(vinyl morpholinone), poly(vinyl alcohol), and mixturesand copolymers thereof. Further polymers suitable for use in theabsorbent core include natural and modified natural polymers, such ashydrolyzed acrylonitrile-grafted starch, acrylic acid grafted starch,methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, andthe natural gums, such as alginates, xanthum gum, locust bean gum, andthe like. Mixtures of natural and wholly or partially syntheticabsorbent polymers can also be useful in the present invention. Suchhigh-absorbency materials are well known to those skilled in the art andare widely commercially available.

The high absorbency material may be in any of a wide variety ofgeometric forms. As a general rule, it is preferred that the highabsorbency material be in the form of discrete particles. However, thehigh absorbency material may also be in the form of fibers, flakes,rods, spheres, needles, or the like. As a general rule, the highabsorbency material is present in the absorbent body in an amount offrom about 5 to about 90 weight percent based on total weight of theabsorbent body.

A hydrophilic wrap sheet may be employed to help maintain the structuralintegrity of the absorbent body 18. For example, the hydrophilic wrapsheet may be a tissue wrap sheet, a nonwoven wrap sheet, a nonwovenlaminate wrap sheet, etc. The wrap sheet is typically placed about theabsorbent body over at least two major facing surfaces thereof andcomposed of an absorbent cellulosic material, such as creped wadding ora high wet-strength tissue. The wrap sheet can be configured to providea wicking layer which helps to rapidly distribute liquid over the massof absorbent fibers constituting the absorbent body 18. Another layer orlayer scan be incorporated between the liner 14 and the absorbent body18, such as a surge layer and/or transfer layer, etc.

According to embodiments of the present invention, the treatmentcomposition can be included on or within the absorbent article 10,particularly on areas of the article 10 that may come into closeproximity to the skin of the wearer. For example, the treatmentcomposition can be applied on or within the body facing surface 16 ofthe body side liner 14, such as by using the application techniquesdiscussed above with reference to wipes.

In one embodiment, the treatment composition can be appliedsubstantially uniformly on the entire body facing surface 16.Alternatively, the treatment composition can be applied as discretelocalized deposits on the body facing surface 16 of the article, whichmay be, for example, the body facing surface 16 of the body side liner14, as discussed in greater detail below. It should be appreciated thatthe invention is not limited to an article having a body side liner 14.For example, in certain embodiments, the article may not include a liner14 and the body facing surface may be defined by an absorbent layer ofmaterial. In this case, the treatment composition would be directlyapplied on or within the absorbent layer, the surge layer, and/or thetransfer layer (if present).

The amount of treatment composition may vary widely within the scope ofthe invention. For example, if a body side liner is used, it may bedesired that the treatment composition be present at an add-on weight ofbetween about 0.5% to about 50% of the weight of the body side liner 14.It is desired that the treatment composition remain substantially on thebody facing surface 16 where it can contact and/or transfer to thewearer's skin to provide the desired skin health benefit.

The treatment composition may be in addition to an overall skin wellnesstreatment applied uniformly to the body side liner 14. For example, theliner 14 may be treated with a surfactant that includes a skin wellnessadditive, or a skin wellness additive may be applied in an additionalprocess. Any of the skin wellness additives discussed herein withrespect to the treatment composition may be applied as a separateoverall treatment to the liner 14.

The invention is not limited to any particular treatment composition.The treatment composition may include any combination of emollients, andmay also include one or more waxes. A viscosity enhancer may also beincluded. The treatment composition may include other ingredients aswell.

The emollients act as lubricants to reduce the abrasiveness of the bodyside liner to the skin and, upon transfer to the skin, help to maintainthe soft, smooth and pliable appearance of the skin. Suitable emollientswhich can be incorporated into the treatment composition include oilssuch as petroleum based oils, vegetable based oils, mineral oils,natural or synthetic oils, silicone oils, lanolin and lanolinderivatives, kaolin and kaolin derivatives and the like and mixturesthereof; esters such as cetyl palmitate, stearyl palmitate, cetylstearate, isopropyl laurate, isopropyl myristate, isopropyl palmitateand the like and mixtures thereof; glycerol esters; ethers such aseucalyptol, cetearyl glucoside, dimethyl isosorbicide polyglyceryl-3cetyl ether, polyglyceryl-3 decyltetradecanol, propylene glycol myristylether and the like and mixtures thereof; alkoxylated carboxylic acids;alkoxylated alcohols; fatty alcohols such as octyldodecanol, lauryl,myristyl, cetyl, stearyl and behenyl alcohol and the like and mixturesthereof. For example, a particularly well suited emollient ispetrolatum. Other conventional emollients may also be added in a mannerwhich maintains the desired properties of the treatment composition setforth herein.

To provide the improved stability and transfer to the skin of thewearer, the treatment composition may include from about 5 to about 95weight percent, desirably from about 20 to about 75 weight percent, andmore desirably from about 40 to about 60 weight percent of theemollient.

The wax in the treatment composition, when included, can primarilyfunction as an immobilizing agent for the emollient and any activeingredient. In addition to immobilizing the emollient and reducing itstendency to migrate, the wax in the treatment composition provides atackiness to the lotion formulation which improves the transfer to theskin of the wearer. The presence of the wax also modifies the mode oftransfer in that the treatment composition tends to fracture or flakeoff instead of actually rubbing off onto the skin of the wearer whichcan lead to improved transfer to the skin. The wax may further functionas an emollient, occlusive agent, moisturizer, barrier enhancer andcombinations thereof.

Suitable waxes which can be incorporated into the lotion formulationinclude animal, vegetable, mineral or silicone based waxes which may benatural or synthetic such as, for example, bayberry wax, beeswax, C30alkyl dimethicone, candelilla wax, carnauba, ceresin, cetyl esters,esparto, hydrogenated cottonseed oil, hydrogenated jojoba oil,hydrogenated jojoba wax, hydrogenated microcrystalline wax, hydrogenatedrice bran wax, Japan wax, jojoba butter, jojoba esters, jojoba wax,lanolin wax, microcrystalline wax, mink wax, montan acid wax, montanwax, ouricury wax, ozokerite, paraffin, PEG-6 beeswax, PEG-8 beeswax,rezowax, rice bran wax, shellac wax, spent grain wax, spermaceti wax,steryl dimethicone, synthetic beeswax, synthetic candelilla wax,synthetic carnauba wax, synthetic Japan wax, synthetic jojoba wax,synthetic wax, and the like and mixtures thereof. For example, aparticularly well suited wax includes about 70 weight percent ceresinwax, about 10 weight percent microcrystalline wax, about 10 weightpercent paraffin wax and about 10 weight percent cetyl esters (syntheticspermaceti wax).

To provide the improved transfer to the skin of the wearer, thetreatment composition may include from about 5 to about 95 weightpercent, desirably from about 25 to about 75 weight percent, and moredesirably from about 40 to about 60 weight percent of the wax. Treatmentcompositions, which include an amount of wax less than the recitedamounts, tend to have lower viscosities which undesirablely leads tomigration of the lotion. Whereas, treatment compositions which includean amount of wax greater than the recited amounts tend to provide lesstransfer to the wearer's skin.

A viscosity enhancer may be added to the treatment composition toincrease the viscosity to help stabilize the formulation on the bodyfacing surface 16 of the body side liner 14 and thereby reduce migrationand improve transfer to the skin. Desirably, the viscosity enhancerincreases the viscosity of the treatment composition by at least about50 percent, more desirably at least about 100 percent, even moredesirably by at least about 500 percent, yet even more desirably by atleast about 1000 percent, and even more desirably by at least about 5000percent. Suitable viscosity enhancers which can be incorporated into thetreatment composition include polyolefin resins, lipophilic/oilthickeners, ethylene/vinyl acetate copolymers, polyethylene, silica,talc, colloidal silicone dioxide, zinc stearate, cetyl hydroxy ethylcellulose and other modified celluloses and the like and mixturesthereof.

To provide the improved transfer to the skin of the wearer, thetreatment composition may include from about 0.1 to about 25 weightpercent, desirably from about 5 to about 20 weight percent, and moredesirably from about 10 to about 15 weight percent of the viscosityenhancer for reduced migration and improved transfer to the wearer'sskin.

If it is desired that the treatment composition treat the skin, it canalso include an active ingredient such as a skin protectant. Skinprotectants may be a drug product which protects injured or exposed skinor mucous membrane surface from harmful or irritating stimuli. Suitableactive ingredients, in addition to those mentioned above as suitableemollients, which can be incorporated into the lotion formulationinclude, but are not limited to, allantoin and its derivatives, aluminumhydroxide gel, calamine, cocoa butter, dimethicone, cod liver oil,glycerin, kaolin and its derivatives, lanolin and its derivatives,mineral oil, shark liver oil, talc, topical starch, zinc acetate, zinccarbonate, and zinc oxide and the like, and mixtures thereof. Thetreatment composition may include from about 0.10 to about 95 weightpercent of the active ingredient depending upon the skin protectant andthe amount desired to be transferred to the skin.

In order to better enhance the benefits to the wearer, additionalingredients can be included in the treatment composition. For example,the classes of ingredients that may be used and their correspondingbenefits include, without limitation: antifoaming agents (reduce thetendency of foaming during processing); antimicrobial actives;antifungal actives; antiseptic actives; antioxidants (productintegrity); astringents—cosmetic (induce a tightening or tinglingsensation on skin); astringent—drug (a drug product which checks oozing,discharge, or bleeding when applied to skin or a mucous membrane andworks by coagulating protein); biological additives (enhance theperformance or consumer appeal of the product); colorants (impart colorto the product); deodorants (reduce or eliminate unpleasant odor andprotect against the formation of malodor on body surfaces); otheremollients (help to maintain the soft, smooth, and pliable appearance ofthe skin by their ability to remain on the skin surface or in thestratum corneum to act as lubricants, to reduce flaking, and to improvethe skin's appearance); external analgesics (a topically applied drugthat has a topical analgesic, anesthetic, or antipruritic effect bydepressing cutaneous sensory receptors); film formers (to hold activeingredients on the skin by producing a continuous film on skin upondrying); fragrances (consumer appeal), silicones/organomodifiedsilicones (protection, tissue water resistance, lubricity, tissuesoftness), oils (mineral, vegetable, and animal); natural moisturizingagents or natural moisturizing factors (NMF) and other skin moisturizingingredients known in the art; opacifiers (reduce the clarity ortransparent appearance of the product); powders (enhance lubricity, oiladsorption, provide skin protection, astringency, opacity, etc.); skinconditioning agents; solvents (liquids employed to dissolve componentsfound useful in the cosmetics); and surfactants (as cleansing agents,emulsifying agents, solubilizing agents, and suspending agents).

The present invention may be better understood with reference to thefollowing examples.

EXAMPLES

In vitro models were developed for screening quorum sensing inhibitorycompounds/products against Candida albicans SC5314 to identify potentialquorum sensing inhibitors. Potential quorum sensing inhibitorycompounds/products were not only sourced from commercial analogs ofquorum sensing molecules, natural antifungal botanicals and antifungaldrugs, but also by synthesizing the analogs of farnesol and developingwater soluble products.

Generally, these Examples presented the following key findings:

1. An in vitro model was established for screening quorum sensinginhibitory compounds against C. albicans SC5314;

2. Eight farnesol analogs were synthesized and screened by the in vitromodel;

4. An in vitro model was established for screening quorum sensinginhibitory compounds against C. albicans SC5314; and

5. Two synthesized farnesol analogs (#1 and #2) significantly reducedthe death rate of Caenorhabditis elegans glp4;sek1 4 infected with C.albicans SC5314.

Test Methods

In these examples, the YPD agar consisted of 10.0 g of peptone, 5.0 g ofYeast extract, 10.0 g of glucose, 10.0 g of agar, and 1.0 L of deionizedwater, which was prepared by mixing all ingredients and then sterilizingvia autoclave at 115° C. for 30 min.

The YPD broth consisted of 10.0 g of peptone, 5.0 g of Yeast extract,10.0 g of glucose, and 1.0 L of deionized water, which was prepared bymixing all ingredients and then sterilizing via autoclave at 115° C. for30 min.

The mGSB broth consisted of 1.0 g of peptone, 2.0 g of KH₂PO₄, 1.0 g of(NH₄)₂SO₄, 0.05 g of MgSO₄.7H₂O, 0.05 g CaCl₂.2H₂O, and 1.0 L ofdeionized water, which was prepared by mixing all ingredients and thensterilizing via autoclave at 121° C. for 15 min. After cool down, afilter sterilized 30 ml 50% glucose solution (w/v) and 0.4 ml GPPvitamin stock was added, which contained the following (per 100 ml of20% ethanol): 2 mg of biotin, 20 mg of thiamine-HCl, and 20 mg ofpyridoxine-HCl.

The NGM agar consisted of 2.5 g of peptone, 3.0 g of NaCl, 17 g of agar,and 975 mL of deionized water, which was prepared by mixing allingredients and then sterilizing by autoclave at 121° C. for 15 min.After cool down, sterilized 25 ml of KPO₄ buffer (400 mM KH₂PO₄ and 100mM K₂HPO₄), 0.1% 1 M MgSO₄ (v/v), 0.1% 1 M CaCl₂ (v/v), filtersterilized 100 mg/ml streptomycin, and 0.1%5 mg/ml cholesterol inethanol (v/v) were added.

The M9 buffer consisted of 3.0 g of KH₂PO₄, 6.0 g of Na₂HPO₄, 5.0 g ofNaCl, and 1 L of deionized water, which was prepared by mixing allingredients and then sterilizing by autoclave at 121° C. for 15 min.After cool down, 1 mL of filter sterilized 1 M MgSO₄ was added.

1. Development of In Vitro Screening Model

a) Develop Protocols for Preparation of Single Cell Suspensions of C.albicans

The growth of Candida albicans SC5314 in two media, Yeast ExtractPeptone Dextrose broth (commonly known as YPD broth), and modifiedglucose salts biotin broth (commonly known as mGSB broth), was examinedduring incubation at 30° C. FIG. 3 shows that SC5314 reached stationaryphase after 24 h incubation at 30° C. in both media. The percentage ofsinglet cells decreased initially, and then increased after 24 h in bothmedia. The percentage of singlet cells in YPD broth exceeded 80% after48 h; whereas that in mGSB broth was around 60-70% after 30 h-54 hincubation.

Based on the results in FIG. 3, single cell suspensions of SC5314 wasprepared as follows. Stock culture of C. albicans SC5314 was streakedonto YPD agar (YPDA) and incubated at 30° C. overnight. Single colonieswere subcultured in YPD broth (YPDB) and incubated 30° C., 200 rpmovernight. Overnight culture in YPDB was subcultured in YPD broth againand incubated 30° C., 200 rpm 48 h. Cells were collected bycentrifugation (4000 g 10 min) at 4° C., washed three times with sterilewater, and then resuspended in sterile water a final concentration of10⁹ colony-forming unit/ml (cfu/ml). The suspension were stored at 4° C.at least 1 d, then subcultured into YPDB to a final concentration of 10⁶cfu/ml. After 48 h incubation, cell suspension was examined under themicroscope for single cell percentage. When the single cell percentageexceeded 80%, cells were collected and washed three times with water,then resuspended in water to a final concentration of 10⁹ cfu/ml, andstored at 4° C. for no more than a month.

b) Develop Protocols for Determination of the Percentage of Germ TubesFormed (GTF %)

Germinated yeast cells generally tend to aggregate, making it difficultto count the total number of cells during the in vitro screening. Todisaggregate the cells, various approaches were attempted, such asvortexing with glass beads, sonication, addition of dithiothreitol (0.1mM to 0.4 mM) and glutathione (reduced, 5 mM to 25 mM), and storage atvarious temperatures (4° C., 15° C., 20° C., 25° C.). Gooddisaggregation was observed only for storage at 15° C. for 20 h, as seenmicroscopically.

Two approaches were taken to determine the percentage of cells with germtubes formed (GTF %). One way was to count the total cells at the startof incubation, and count the ungerminated cells after incubation, thencalculate the GTF % as (1−ungerminated cells/total cells at 0 h)*100.Another way was to store the samples at 15° C. for 20 h afterincubation, then count the germinated cells and total cells afterdisaggregation, then calculated the GTF % as (germinated cells/totalcells after storage)*100. No significant difference was observed for theGTF % of C. albicans in a screening medium (11 mM imidazole buffer, 3 mMMgSO4, and 2.6 mM N-acetyl-D-glucosamine) determined by the two methods.Therefore, for practical purposes, the GTF % was determined by the firstmethod, that is, GTF %=(1−ungerminated cells/total cells at 0 h)*100,for the in vitro screening discussed herein.

c) Select Screening Media for In Vitro Screening

A screening medium, containing 11 mM imidazole buffer, 3 mM MgSO4, and2.6 mM N-acetyl-D-glucosamine (GlcNAc) has been used to study the effectof farnesol analogs on the germ tube formation of C. albicans. Here, thegerm tube formation of C. albicans in modified screening media wasassessed with various concentrations of imidazole buffer (10 mM, 30 mMand 50 mM) and MgSO4 (0.5 mM, 1.5 mM and 3 mM). Table 1 shows that theGTF % deceased as the concentration of imidazole buffer increased;whereas the GTF % increased as the concentration of MgSO4 increased. Ittook 2 h to 3 h for the GTF % to reach above 80%. For practicalpurposes, the screening medium, containing 11 mM imidazole buffer, 0.5mM MgSO4, and 2.6 mM N-acetyl-D-glucosamine (GlcNAc) was adopted for invitro screening the quorum sensing inhibitory effect of farnesolcompounds.

Table 1 shows the effect of concentrations of imidazole buffer and MgSO4on the germ tube formation (GTF %) of C. albicans cells at 37° C. inscreening media (pH 6.5) with 2.6 mM N-acetyl-D-glucosamine.

TABLE 1 Imidazole GTF % buffer Mg²⁺ 1.5 h 2 h 2.5 h 3 h 10 mM 0.5 mM32.0 84.8 1.5 mM 34.4 88.8 3.0 mM 38.0 86.8 30 mM 0.5 mM 29.2 54.8 82.81.5 mM 39.2 66.8 84.4 3.0 mM 34.0 64.0 92.4 50 mM 0.5 mM 18.8 38.4 65.276.4 1.5 mM 22.8 41.2 66.8 80.0 3.0 mM 10.0 62.0 68.8 85.6 Note: GTF %was calculated as the 1-(ungerminated cells/total cells at 0 h) %

d) Effect of Quorum Sensing Molecules on Lag Phase of C. albicans

FIG. 4 shows that 100 μM farnesol or 100 μM tyrosol had little effect onthe growth of C. albicans SC5314 in YPD broth at 37° C. for 6 h (where“CK” is a control sample of C. albicans SC5314 in YPD broth at 37° C.for 6 h). Those results confirm no increase of cells occurred during theperiod of the in vitro screening.

Synthesis of Farnesol Analogs

Eight farnesol analogs were synthesized, the structures of whichcorrespond to the Exemplary Farnesol Analogs 1-8 discussed above. FIG. 5shows the reaction mechanisms utilized in the synthesis of the ExemplaryFarnesol Analogs 1-8.

Table 2 shows the effect of farnesol, farnesol analogs and tyrosolanalogs on the germ tube formation (GTF %) of C. albicans SC5314.

TABLE 2 GTF % (mean ± SEM, n = 2) Compounds CAS No MW 100 μM 200 μME,E-farnesol 106-28-5 222.37 44.0 ± 3.1 18.4 ± 2.9 trans-nerolidol40716-66-3 222.37 92.4* 51.6 ± 1.8 farnesyl acetate 29548-30-9 264.451.9 ± 2.1 36.8 ± 0.8 4-hydroxy phenyl acetic 156-38-7 152.15 93.1* 86.2± 1.6 acid 2-hydroxy phenyl acetic 614-75-5 152.15 90.3* 71.3 ± 2.5 acid3-Methoxy-4- 1477-68-5 203.67 95.7* 86.4 ± 3.3 hydroxyphe- nylethylamine hydroxytyrosol 10597-60-1 154.16 78.0* 84.9 ± 0.1 β-phenylethanol60-12-8 122.16 91.7* 84.5 ± 0.3 salidroside 10338-51-9 300.3 93.2* 78.0± 5.9 #1 synthesized analog 322.44 55.9 ± 8.2 31.2 ± 5.0 #2 synthesizedanalog 394.55 71.2 ± 2.9 33.9 ± 0.6 #3 synthesized analog 380.52 66.9 ±1.5 32.9 ± 1.0 #4 synthesized analog 366.5 59.2 ± 4.8 31.1 ± 8.2 #5synthesized analog 294.48 73.8 ± 4.8 53.6 ± 3.0 #6 synthesized analog280.45 75.1 ± 0.5 51.1 ± 3.2 #7 synthesized analog 266.42 72.6 ± 1.758.8 ± 2.1 #8 synthesized analog 384.51 76.6 ± 0.3 66.3 ± 0.9 Control82.8 ± 0.6 *One replicate

In Vitro Screening

Caenorhabditis elegans glp4;sek1 was used as the model for in vitroscreening. Breger et al. (Breger, J.; Fuchs, B. B.; Aperis, G.; Moy, T.I., Ausubel, F. M., Mylonakis, E.; “Antifungal chemical compoundsidentified using a C. elegans pathogenicity assay.” PLoS Pathogens 3:168-178; 2007) reported that the glp-4 mutation rendered the strainincapable of producing progeny at 25° C., and the sek-1 mutationenhanced the sensitivity of the strain to various pathogens, therebydecreasing the time for screening assays. It was observed that noprogenies was produced by the Caenorhabditis elegans glp4;sek1 strainafter 3 d incubation at 25° C.

The synchronization of C. elegans was achieved by collecting the eggsand arresting the larvae at L1 stage. The commonly used bleach treatmentwas able to release the eggs from the adult worms. However, it wasobserved that the released eggs were not always able to hatch aftertreated with sodium hypochlorite (0.2, 0.3, 0.4, 0.5, 0.7 or 1%) for 3-5min. A modified egg laying method was developed to synchronize worms toL1 stage. In brief, stock cultures of C. elegans glp4;sek1, maintainedon Nematode Growth Media plates (NGM plates), were subcultured onto NGMplates with OP50 and incubated at 15° C. for 6-9 days. Then a chunk (1cm²) of agar with gravid adults was subcultured again onto NGM plateswith OP50 and incubated at 15° C. After incubation of 3-7 days, theworms were gently washed off with 3 ml of M9 buffer on the rotatingplatform (100 rpm). The plate was tilted on its lid to allow the liquidand worms drain to one side of the plate. The liquid and worms wereaspirated off. The plate was washed again with M9 buffer three moretimes to remove OP50 as much as possible. After washing, the plate wasincubated at 25° C. overnight to let the eggs hatch overnight. Sincethere was no OP50, the larvae were arrested at the L1 stage.

The live C. elegans glp4;sek1 was quite curvy; whereas the dead C.elegans glp4;sek1 tended to be straight, and in most cases the deadworms with the hyphae of C. albicans pieced through the body. The curvyshape and movement after shaking were used as the criteria for live.

Results from initial screening showed that the death rate of C. elegansglp4;sek1 infected with C. albicans SC5314 increased over time (Table3). The presence of 0.4 mM farnesol reduced the death rate slightly. Thehigher concentration of farnesol resulted in higher death rate of theworm. This implies that the farnesol at higher concentrations may betoxic to the worm.

Table 3 shows the death rate of C. elegans glp4;sek1 infected with C.albicans SC5314 during incubation in 96 well plates

TABLE 3 % change in the death rate Concen- compared to the controlCompounds tration day 1 day 4 day 5 farnesol 0.4 mM   −4 −16 −19 1 mM−12 14 10 2 mM −8 19 8 3 mM −21 23 12 Death rate of control (%) 39 72 81

Seven farnesol analogs at various concentrations were screened in vitro(Table 4). Analog #1, at concentrations of 0.4 mM to 2 mM, significantlyreduced the death rate of C. elegans glp4;sek1 infected with C. albicansSC5314; however, Analog #1 increased the death rate when it was 3 mM.Analogs #2, at concentrations of 0.4 mM to 3 mM, also reduced the deathrate significantly. The other three synthesized analogs (#3, #4 and #5)did not have significant effect on the death of the worms.Trans-nerolidol and farnesyl acetate, at the tested four concentrations,however, increased the death rate of the worm significantly. Table 4shows the death rate of C. elegans glp4;sek1 infected with C. albicansSC5314 in the presence of farnesol analogs in the 96 well plates at 25°C.

TABLE 4 % change in the death rate Concen- compared to the controlFarnesol analogs tration 4 days 5 days #1 synthesized 0.4 mM −43 ± 8 −30 ± 2  analog 1.0 mM −33 ± 5  −29 ± 11   2.0 mM* −23 ± 4  −34 ± 11 3.0 mM 20 ± 3  10 ± 9  #2 synthesized 0.4 mM −36 ± 4  −38 ± 2  analog1.0 mM −28 ± 5  −29 ± 10   2.0 mM* −39 ± 11  −39 ± 11  3.0 mM −40 ± 0 −40 ± 4  #3 synthesized 0.4 mM −6 ± 7  10 ± 3  analog 1.0 mM 1 ± 6 3 ± 82.0 mM −12 ± 9   9 ± 10 3.0 mM −2 ± 2  7 ± 1 #4 synthesized 0.4 mM 8 ± 87 ± 1 analog 1.0 mM −3 ± 3  −1 ± 4  2.0 mM 4 ± 8  8 ± 11 3.0 mM 7 ± 4 10± 5  #5 synthesized 0.4 mM −3 ± 6  −6 ± 3  analog 1.0 mM 2 ± 3 9 ± 1 2.0mM −8 ± 1  2 ± 2 3.0 mM −4 ± 4  4 ± 1 trans-nerolidol 0.4 mM 11 ± 4  4 ±5 1.0 mM 3 ± 7 −8 ± 5  2.0 mM 25 ± 10 10 ± 2  3.0 mM 7 ± 0 9 ± 9farnesyl acetate 0.4 mM 10 ± 6  4 ± 3 1.0 mM 27 ± 7  15 ± 7  2.0 mM 21 ±5  9 ± 2 3.0 mM 24 ± 9   7 ± 10 Note: results are average of tworeplicates except those indicted by * that are mean of three replicates

The toxicity of the selected compounds/products were tested using the C.elegans glp4;sek1 fed on E. coli OP50 (Table 5). The results showed thattrans-nerolidol and farnesyl acetate at 2 mM was toxic to the worm,which may explain why those two compounds increased the death rate of C.elegans. The five synthesized analogs at 2 mM showed no toxicity againstC. elegans. The death rate of 2 mM farnesol was slightly higher than thecontrol. Table 5 shows the death rate of C. elegans glp4;sek1 fed on E.coli OP50 in the presence of screened compounds at 25° C.

TABLE 5 Compounds/products Concentration Death rate (%) Control / 4 ±0.6 farnesol 2 mM 7 farnesyl acetate 2 mM 12  trans-nerolidol 2 mM 23 #1 synthesized analog 2 mM 3.3 ± 1.2  #2 synthesized analog 2 mM 4 ± 0.6#3 synthesized analog 2 mM 6 #4 synthesized analog 2 mM 2 #5 synthesizedanalog 2 mM 4 Note: Results of Control, #1 and #2 products were mean ofthree replicates, results of others were single measurement.

Water soluble products were synthesized and had inhibitory effect on thequorum sensing of C. albicans in vitro.

EXPERIMENTAL 1. Maintenance of Candida albicans SC5314

Candida albicans SC5314 was streaked onto YPD agar (YPDA) and incubatedat 30° C. overnight. Single colonies were subcultured in YPD broth(YPDB) and incubated 30° C., 200 rpm overnight. Glycol stocks ofovernight culture in YPDB were prepared, and stored in −20° C.

2. Maintenance of Caenorhabditis elegans

Caenorhabditis elegans glp4;sek1 was maintained by subculturing on E.coli OP50 on NGM plates at 15° C. for 7 days. Those can be stored at 15°C. for up to 2 months.

3. In Vitro Screening of Compounds

The in vitro screening assay was based on the N-acetylglucosamine(GlcNAc)-triggered differentiation assay (Hornby et al., “Quorum sensingin the dimorphic fungus Candida albicans is mediated by farnesol;”Applied and Environmental Microbiology 67:2982-2992; 2001), whichincluded 0.56 ml of 0.1 M imidazole buffer (pH6.5), 0.15 ml of 0.1 MMgSO₄, 0.13 ml of 0.1 M GlcNAc, and 4.16 ml of sterilized water.Bioassays of quorum sensing candidates were conducted by the addition ofthe chemical, as a solution in 100% methanol, to the bioassay media; thefinal concentration of methanol was no greater than 1%.

4. In Vitro Screening of Compounds

The In vitro screening assay, based on the method of Tampakakis et al(Tampakakis, E.; Okoli, I.; Mylonakis, E.; “A C. elegans-based, wholeanimal, in vivo screen for the identification of antifungal compounds.”Nature Protocols 3:1925-1931; 2008), is described as follows:

a) Preparation of Worms

L1 worms, which were prepared by the modified egg-laying method, werecollected by centrifugation at 675 g for 30 s at room temperature, andthe supernatant was removed. Worms were resuspended in M9 buffer andinoculated on NGM agar plates with OP50, ˜1000 worms per plate. After2-3 days incubation at 25° C., the worms were washed off with M9 bufferfor the in vitro screening assay.

b) Preparation of C. albicans

Stock cultures of C. albicans SC5314 was subcultured into 3 ml of YPDbroth and incubated at 30° C. Then the overnight culture in broth wasspread onto YPD agar, and incubated at 30° C. The 24 h old lawn ofSC5314 was used to feed worms for 2 h at 25° C. The control were wormsfed on OP50.

c) In Vitro Screening Assay

The worms were washed off the YPD plates and washed twice with M9buffer. The worms were resuspended in screening media, M9 buffer with0.3% Tween 80. The worm suspension (50 μl) was dispensed into the wellsof 96-well plates, 20-30 worms/well. Aliquots (50 μl) of compounds inscreening media were added to wells, 5 wells each compound. The 96 wellplates were incubated at 25° C. for up to 5 days. Live and dead wormswere counted during incubation, and the death rates of worms werecalculated.

While the invention has been described in detail with respect to thespecific embodiments thereof, it will be appreciated that those skilledin the art, upon attaining an understanding of the foregoing, mayreadily conceive of variations and equivalents to these embodiments.Accordingly, the scope of the present invention should be assessed asthat of the appended claims and any equivalents thereto.

What is claimed is:
 1. A farnesol analog comprising a hydrophilic endgroup attached to farnesol via a covalent linkage, wherein thehydrophilic end group defines a hydroxyl end group, and wherein thecovalent linkage comprises an ester group or an ether group, wherein thefarnesol analog comprises one of the structures:

where n is an integer from 1 to 8; m is an integer from 1 to 8; and p isan integer from 1 to
 100. 2. The farnesol analog as in claim 1, whereinthe covalent linkage comprises an ester group.
 3. The farnesol analog asin claim 1, wherein n is 2, 3, or
 4. 4. The farnesol analog as in claim3, wherein the hydrophilic end group comprises an ester group.
 5. Thefarnesol analog as in claim 1, wherein n is 2, 3, or 4; and wherein m is2, 3, or
 4. 6. The farnesol analog as in claim 1, wherein the covalentlinkage comprises an ether group, and wherein the hydrophilic end groupdefines a hydroxyl end group.
 7. The farnesol analog as in claim 1,wherein the farnesol analog has a solubility in water that is 10 gramsper 100 grams of water or greater.
 8. A web comprising a plurality offibers, wherein the web is coated with a treatment composition, thetreatment composition comprising a farnesol analog according to claim 1.9. An absorbent article comprising: a liquid impermeable outer cover; aliquid permeable bodyside liner, wherein the bodyside liner comprisesthe web according to claim 8; and an absorbent body disposed between theouter cover and bodyside liner.
 10. A method of forming a farnesolanalog that is soluble in water from a farnesol molecule having ahydroxyl group, the method comprising: covalently attaching ahydrophilic end group to the farnesol molecule via reaction with itshydroxyl group to form a covalent linkage, wherein the hydrophilic endgroup defines a hydroxyl end group, and wherein the covalent linkagecomprises an ester group or an ether group, wherein the farnesol analogcomprises one of the structures:

where n is an integer from 1 to about 8; m is an integer from 1 to 8;and p is an integer from 1 to
 100. 11. The method as in claim 10,wherein the covalent linkage comprises an ester group formed via anesterification reaction between the hydroxyl group of the farnesolmolecule and a carboxylic acid functional molecule.
 12. The method as inclaim 11, further comprising: reacting the carboxylic acid end groupwith a glycol via a second esterification reaction to form a farnesolanalog having a hydroxyl group covalently attached via two esterlinkages.
 13. The method as in claim 12, wherein the glycol is selectedfrom the group consisting of ethylene glycol, propylene glycol, andbutane-1,4-diol.
 14. The method as in claim 10, wherein the covalentlinkage comprises an ether group formed by reacting farnesol with analcohol via a dehydration reaction to form the ether group.
 15. Themethod as in claim 14, wherein the alcohol is a glycol selected from thegroup consisting of ethylene glycol, propylene glycol, andbutane-1,4-diol.
 16. The method as in claim 14, wherein the hydrophilicend group comprises a sugar.
 17. A wipe comprising the web according toclaim 8.